Abstract
Battino D, Tomson T, Bonizzoni E, Craig J, Perucca E, Sabers A, Thomas S, Alvestad S, Perucca P, Vajda F; EURAP Collaborators. JAMA Neurol. 2024;81(5):481-489. doi:10.1001/jamaneurol.2024.0258. PMID: 38497990; PMCID: PMC10949148. Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, setting, and participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main outcomes and measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.
Commentary
Anatomical and behavioral teratogenicity of antiseizure medications (ASMs) remains a major concern for women with epilepsy (WWE) in reproductive age and their health care providers. The current study by Battino et al, 1 included 2485 additional pregnancies than previously reported in the 2018 analysis of their cohort data, 2 and aimed to determine the comparative risk of major congenital malformations (MCMs) associated with 8 frequently prescribed ASM monotherapies.
The EURAP international registry (Registry of Antiepileptic Drugs and Pregnancy) currently includes data from 28 553 pregnancies exposed to ASMs from 47 countries. From June 1999 to October 2022, a total of 10 121 pregnancies were exposed to ASM monotherapy, with complete follow-up data. Of these, 9840 pregnancies from 8483 women (mean [range] age, 30.1 [14.1-55.2] years) had been reported as exposed to the 8 most frequently used ASMs, including 1247 WWE with two or more pregnancies, and 146 twin pregnancies and 1 triplet pregnancy, each offspring considered separate pregnancies. 1
EURAP had already shown that the overall prevalence of MCM in ASM monotherapy-exposed pregnancies decreased by 39% over time, from 6.0% in 2000 to 2005 to 4.4% in 2010 to 2013, to 3.7%, during the period of 2015 to 2022.1,3 Over the past 25 years, there have been some changes in trends for ASM prescription, with decreased use of valproic acid, phenobarbital, and carbamazepine and increased use of lamotrigine and levetiracetam.1,3 During the same period, there was increased awareness about folic acid and more efficient prescription, although periconceptional folate supplementation and reduction in teratogenicity rates have not been directly related, including in the current study.1,2,4
In 9840 ASM-exposed pregnancies, cardiac malformations were the most frequently reported, for all ASMs, particularly for intrauterine exposure to phenytoin, phenobarbital, topiramate, and valproate. Parental history of MCM was associated with a 3.4-fold risk increase in risk of MCM in the offspring, as previously described in the EURAP previous analysis. In the additional 281 pregnancies exposed to other less frequently used ASMs monotherapy, 7 offsprings presented with MCMs, with an overall prevalence of 2.5%: Clobazam (N = 1/19), Gabapentin (N = 1/37), Primidone (N = 3/44), Vigabatrin (N = 1/5), Zonisamide (N = 1/5). No MCMs were reported in pregnancies exposed to lacosamide (N = 31), Brivaracetam (N = 2), Eslicarbazepine (N = 7), Pregabalin (N = 7).
The teratogenicity risk of most prescribed ASM follows a (still evolving) spectrum, being considered low for levetiracetam and lamotrigine, intermediate for carbamazepine, oxcarbazepine, and zonisamide, and relatively high for topiramate, phenobarbital, and clobazam. Pregnancy outcome registries in WWE have shown that the risk of MCM (and of behavior or cognitive teratogenicity) is highest and dose-dependent for valproic acid. 5
Higher MCM rates had been previously reported with increasing dosage at the time of conception for carbamazepine, lamotrigine, valproic acid, and phenobarbital, 2 but the current extended analysis did not demonstrate such dose effect for lamotrigine, 1 which brings further reassurance for an ASM considered among the safest. Indeed, offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine had the lowest prevalence of MCMs compared to other ASMs. Whereas one of these three safer ASMs could potentially adequately control seizures and enable safe conception for a majority of WWE, those with drug-resistant epilepsies that might fail treatment still face the challenge of added risks with need for ASM polytherapy or new ASM without sufficient pregnancy safety information.
The rate of MCMs in offspring of healthy women is estimated as 1% to 2% of live births. Several pregnancy registries worldwide are collecting data on ASMrelated MCMs and other pregnancy-related outcomes in WWE. However, these registries have important methodological differences in recruitment, ascertainment, inclusion and exclusion criteria, MCM classification, and follow-up, which may influence the results and prevent meaningful pooling of data. Registries that included follow-up of offspring for 1 year compared to registries that limited follow-up to 2 months after birth can identify an additional 15% in total cases of MCM. 2 Moreover, exposure to ASM during pregnancy has most often been determined by the mother's medication dosage rather than plasma level, which would more accurately reflect fetal exposure to the medication. As it remains equally important to understand dose-effect and type of ASM, information from prospective cohorts and harmonized criteria for evaluation worldwide will be ultimately meaningful. Moreover, the total number of pregnancies exposed to the different ASM in each registry is very discrepant; thus, percentage descriptions should also be regarded in relation to the total pregnancies for each medication. Another important observation is that parental history of MCM can be associated with an almost three times increase in the odds of MCM,1,2 and details on this information might vary across studies. This suggests a genetic predisposition to malformations or an individual's susceptibility to the teratogenic effects of ASM. 2
Footnotes
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author received no financial support for the research, authorship, and/or publication of this article.
